The role of serotonin receptor subtypes in treating depression: a review of animal studies.

Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

RATIONALE:

Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs.

OBJECTIVE:

Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed.

RESULTS:

Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT(1A), 5-HT(1B), 5-HT(2C), 5-HT(4), and 5-HT(6) receptors. Also, antagonists at 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(6), and 5-HT(7) receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination.

CONCLUSIONS:

The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.

Schematic representing two ways that 5-HT2C receptors may be involved in producing the behavioral effects of antidepressant drugs. 5-HT2C receptor agonists may produce antidepressant-like behavioral effects by directing stimulating 5-HT2C receptors. This would be a subset of the effects produced by the global stimulation of postsynaptic 5-HT receptors with SSRIs. In contrast, 5-HT2C receptor antagonists may produce antidepressant-like behavioral effects by increasing the release of NE and DA in terminal regions such as the nucleus accumbens by blocking the tonic inhibition of DA and NE release exerted by 5-HT2C receptors